Drug-induced Weight Gain: Schizophrenia and Antipsychotics

Atypical antipsychotics were ushered in with great fanfare. Research demonstrated that they were effective in treating the positive symptoms of schizophrenia (eg, hallucinations, delusions, disorganized speech). Unlike the first generation of neuroleptics, they also addressed schizophrenia's negative symptoms (eg, blunted affect, social withdrawal, diminished motivation). In addition, long-term use did not increase the risk of extrapyramidal symptoms (EPSs), including tardive dyskinesia.

Clozapine, FDA-approved in 1989, was followed by risperidone (1993), olanzapine (1996), quetiapine (1997), ziprasidone (2001), and aripiprazole (2002).¹ Clozapine's association with agranulocytosis had already been demonstrated in the early 1970s when it was approved in Europe. Nevertheless, the agent was effective for refractory schizophrenia, offering hope for those suffering from schizophrenia's most debilitating course.²

The atypicals that followed clozapine seemingly lacked life-threatening side effects. Yet, clinicians tempered their enthusiasm when reports soon followed linking these atypicals to diabetes, weight gain, obesity, dyslipidemia, impaired glucose tolerance, and metabolic syndrome.³

In 2004, the American Diabetes Association, the American Psychiatric Association, the American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity established a consensus panel on schizophrenia and diabetes.⁴ The Table summarizes the panel's findings concerning metabolic risks and atypical antipsychotics.

Schizophrenia and Weight Gain

Independent of medication, schizophrenia always has been associated with weight gain. Many believe that dietary and lifestyle consequences are to blame, although some researchers theorize that schizophrenia itself may be genetically linked to appetite dysregulation.^5,6 Weight-gain pathophysiology is complex and is mediated by monoaminergic, cholinergic, and histaminergic receptors. The interaction of these receptors with schizophrenia is poorly understood.⁷

Up to 50% of patients taking antipsychotics gain weight.⁷ Additionally, weight gain is associated with nonadherence, relapse, and decreased quality of life. Obese individuals, for example, are 13 times more likely to discontinue medications because of drug-induced weight gain.⁷ Although almost all conventional antipsychotics have been linked to weight gain, more weight gain is observed with the atypicals than with conventional agents.

Atypical antipsychotic-induced weight gain tends to be most rapid in the acute phase of treatment but generally plateaus within 1 to 2 years.⁶ Meta-analysis found that patients receiving standard doses of atypical antipsychotics for 10 weeks gained a mean of 9.79 lb with clozapine, 9.13 lb with olanzapine, 6.42 lb with sertindole, 4.6 lb with risperidone, and 0.09 lb with ziprasidone.⁸ Prospective studies revealed that the average weight gain during the first year of treatment was 11.7 to 13.9 lb for clozapine, 15 to 26 lb for olanzapine, 4.4 to 5.1 lb for risperidone, 6.1 to 13.3 lb for quetiapine, and less than 2 lb for aripiprazole and ziprasidone.⁹

Switching Antipsychotics

Consensus guidelines recommend intervening when a patient experiences a weight gain of 5% or more at any time during treatment.⁴ Along with lifestyle interventions, prescribers might consider switching the patient to another atypical. This suggestion creates a clinical dilemma for patients who have improved significantly except for weight gain.⁴ Other practitioners have recommended switch strategies when a patient gains 5 lb over 4 weeks, or when total weight gain exceeds 11 lb.⁷

Abrupt antipsychotic withdrawal is associated with discontinuation reactions, including restlessness, insomnia, anxiety, confusion, nausea, and muscular aches and pains due to cholinergic rebound. Tapering is necessary unless the patient has an acute or severe reaction, such as agranulocytosis.¹⁰ Clinicians should hospitalize patients who require abrupt withdrawal for observation if possible.

Before switching antipsychotics, clinicians need to inform patients of the potential for relapse. If possible, a gradual cross-tapering period lasting several weeks is recommended.⁷ During this time, the dose of the patient's current agent is tapered downward while the new agent is gradually increased. The rate of cross-tapering should be particularly slow for elders, outpatients, and those with a history with severe, unstable, recalcitrant schizophrenia.¹⁰ Studies indicate that weight loss associated with switching agents often exceeds that achieved from adjunctive medications and lifestyle interventions.⁷

Weight-management Strategies

No guidelines exist to manage antipsychotic-induced weight gain. With lifestyle interventions, clinicians may consider prescribing an FDA-approved agent for weight loss: the lipase inhibitor orlistat or the appetite suppressant sibutramine.^6,11 If off-label use is acceptable, topiramate is known for its weight-reducing properties and might be considered, but it has the potential to interact with many drugs used in the mental health setting. Although studies with schizophrenia patients are limited, some practitioners believe that other agents demonstrating weight reduction (eg, fluoxetine, metformin, amantadine, nizatidine) may be potentially beneficial, but prescribing them constitutes off-label use.⁶ Additional research is needed on all of these agents, and clinicians should proceed cautiously on a caseby- case basis, using these drugs because they tend to cause less weight gain rather than using them as treatments to stimulate weight loss.

Given weight gain and the association between obesity and nonadherence, several factors should be considered when selecting agents: adherence history, patient preference, prior responses to treatment, existing comorbidities, family history, cost of and access to interventions, adherence to required monitoring, and side-effect profiles.⁷ The aforementioned consensus panel recommends a monitoring protocol for patients taking atypicals. It can be accessed at http://care.diabetesjournals.org/cgi/content/full/27/2/596.

CATIE

The ongoing Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) is the largest, longest, and most comprehensive double-blind study examining existing schizophrenia therapies and comparing approved drugs. Approximately 1400 participants in 56 sites were randomly assigned to receive olanzapine, quetiapine, risperidone, ziprasidone, or perphenazine. Although previous studies often compared atypicals with haloperidol, the CATIE researchers selected perphenazine as the representative conventional agent because of its increased tolerability and lower EPS risk.^12-14

Desiring a sample that was representative of the 3 million Americans with the disease, the investigators imposed few eligibility restrictions. Researchers will follow participants for 18 months, collecting comprehensive clinical data. The study has 3 phases. Phase 1 focuses primarily on adherence, general outcomes, and side-effect profiles. Phases 2 and 3, which also include a clozapine arm, focus on specific outcomes, such as cognitive functioning, quality of life, reversibility of side effects, and cost-effectiveness.

Phase 1 findings were published in September 2005, some of which were surprising. Specific findings were as follows:

• 74% of the participants discontinued their assigned study medication prior to the end of the 18-month period; discontinuation rates varied: olanzapine, 64%; risperidone, 74%; perphenazine, 75%; ziprasidone, 79%; and quetiapine, 82%
• The time to discontinuation for any cause was longest in the olanzapine group
• The time to discontinuation for intolerable side effects was similar among the groups
• Olanzapine was associated with more weight gain and metabolic effects; 30% of patients on olanzapine gained more than 7% of their baseline weight, compared with 7% to 16% observed in other groups
• Perphenazine discontinuation was more likely associated with EPSs, although the incidence of EPSs was similar among groups
• Fewer hospitalizations occurred in the olanzapine group (11%), compared with the other groups (15%-20%).^12-14

Whereas CATIE established the superior efficacy of olanzapine, it also confirmed that drug's serious side-effect profile, creating clinical efficacy versus side-effect dilemmas.¹⁴ Nevertheless, the high discontinuation rates for all agents highlight the persistent need for new, more tolerable agents.

Final Thought

Preventing and managing weight gain is a priority for patients taking antipsychotic agents. Side-effect profiles associated with conventional and atypical agents are important considerations. Because many patients with severe schizophrenia have limited insight, ongoing monitoring is the norm. Pharmacists often see these patients more frequently than their primary care physicians, and thus they are in a unique position to counsel patients and improve adherence.

Ms. Wick is a senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health. Dr. Zanni is a health-systems consultant and a psychologist based in Alexandria, Va. The views expressed are those of the authors and not those of any government agency.

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